Targeting Glioblastoma Stem Cells via EphA2: Structural Insights into the RNA Aptamer A40s for Precision Therapy.
| Title: | Targeting Glioblastoma Stem Cells via EphA2: Structural Insights into the RNA Aptamer A40s for Precision Therapy. |
|---|---|
| Authors: | Diakogiannaki I; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; D'Amore VM; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; Affinito A; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy.; Donati G; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; Cinquegrana E; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; Quintavalle C; Institute of Experimental Institute of Endotypes in Oncology, Metabolism and Immunology 'G. Salvatore' (IEOMI), Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy.; Mascolo M; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy.; Walter J; Institute for Biochemistry, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.; Betat H; Institute for Biochemistry, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.; Mörl M; Institute for Biochemistry, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.; Di Leva FS; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.; Condorelli G; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy.; Marinelli L; Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy. |
| Source: | Journal of chemical information and modeling [J Chem Inf Model] 2025 Jun 09; Vol. 65 (11), pp. 5635-5648. Date of Electronic Publication: 2025 May 23. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101230060 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-960X (Electronic) Linking ISSN: 15499596 NLM ISO Abbreviation: J Chem Inf Model Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, D.C. : American Chemical Society, c2005- |
| MeSH Terms: | Aptamers, Nucleotide*/chemistry ; Aptamers, Nucleotide*/pharmacology ; Aptamers, Nucleotide*/metabolism ; Neoplastic Stem Cells*/drug effects ; Neoplastic Stem Cells*/metabolism ; Neoplastic Stem Cells*/pathology ; Glioblastoma*/pathology ; Glioblastoma*/drug therapy ; Glioblastoma*/metabolism ; Receptor, EphA2*/metabolism ; Receptor, EphA2*/chemistry ; Receptor, EphA2*/antagonists & inhibitors ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Precision Medicine*; Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor ; Molecular Targeted Therapy |
| Abstract: | EphA2 receptor tyrosine kinase is overexpressed in many solid tumors and serves as a key driver of tumorigenesis and metastasis. It is highly expressed in glioblastoma multiforme, the most aggressive brain tumor in adults, and in its stem cells [glioblastoma stem cells (GSCs)], which contribute to treatment resistance and tumor relapse. In a previous study, we used the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedure, a method for selecting high-affinity nucleic acids to specific targets via iterative selection and amplification, to identify the 2'-fluorinated EphA2-targeting RNA aptamer A40L and a truncated 30-mer derivative, A40s. Both aptamers were able to inhibit GSC growth, stemness, and migration upon EphA2 binding. Here, by integrating computational and experimental methods, the A40s structure was unraveled and its interaction with EphA2 was investigated. Our model offers a blueprint to accelerate the development of optimized A40s variants, advancing next-generation EphA2-targeted anticancer therapies. |
| References: | J Int Med Res. 2014 Feb;42(1):198-204. (PMID: 24398760); J Chem Theory Comput. 2015 Aug 11;11(8):3696-713. (PMID: 26574453); Bioinformatics. 2011 Jul 1;27(13):i85-93. (PMID: 21685106); Mol Ther Oncolytics. 2022 Feb 20;24:729-741. (PMID: 35317513); Biosens Bioelectron. 2022 Oct 1;213:114451. (PMID: 35700603); Nature. 2006 Dec 7;444(7120):756-60. (PMID: 17051156); Mol Ther Nucleic Acids. 2020 Jun 5;20:176-185. (PMID: 32169805); Biomed Res Int. 2015;2015:658712. (PMID: 25866800); Nucleic Acid Ther. 2015 Oct;25(5):227-34. (PMID: 26125598); Int J Mol Sci. 2018 Oct 25;19(11):. (PMID: 30366424); BMC Bioinformatics. 2010 Mar 15;11:129. (PMID: 20230624); Algorithms Mol Biol. 2011 Nov 24;6:26. (PMID: 22115189); Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W135-41. (PMID: 15215366); J Phys Chem B. 2021 Sep 16;125(36):10108-10118. (PMID: 34473508); Oncogene. 2015 Jan 29;34(5):558-67. (PMID: 24488013); Methods Mol Biol. 2016;1380:33-46. (PMID: 26552814); J Mol Graph. 1996 Feb;14(1):33-8, 27-8. (PMID: 8744570); J Phys Chem B. 2009 Oct 8;113(40):13279-90. (PMID: 19757835); J Comput Chem. 2011 Jan 15;32(1):170-3. (PMID: 20645303); Mol Cancer Res. 2005 Oct;3(10):541-51. (PMID: 16254188); World J Clin Oncol. 2023 Apr 24;14(4):138-159. (PMID: 37124134); Biol Pharm Bull. 2017;40(10):1616-1624. (PMID: 28966234); Methods Enzymol. 1996;267:275-301. (PMID: 8743323); NAR Genom Bioinform. 2022 Nov 29;4(4):lqac088. (PMID: 36458023); J Hematol Oncol. 2020 Aug 18;13(1):114. (PMID: 32811512); Br J Cancer. 2008 Oct 7;99(7):1074-82. (PMID: 18797457); Sci Rep. 2023 Nov 13;13(1):19858. (PMID: 37963922); Bioinformatics. 2022 Aug 10;38(16):4042-4043. (PMID: 35758624); RNA. 2019 Feb;25(2):219-231. (PMID: 30420522); J Genet Genomics. 2021 Apr 20;48(4):261-267. (PMID: 33962882); Nucleic Acids Res. 2009 Jul;37(Web Server issue):W277-80. (PMID: 19435882); J Chem Theory Comput. 2011 Sep 13;7(9):2886-2902. (PMID: 21921995); Nat Commun. 2023 Feb 24;14(1):1060. (PMID: 36828844); Nucleic Acids Res. 2011 Apr;39(8):3482-95. (PMID: 21183463); J Nanobiotechnology. 2023 Oct 18;21(1):381. (PMID: 37848888); J Chem Inf Model. 2023 Oct 23;63(20):6183-6191. (PMID: 37805934); Cancer Cell. 2012 Dec 11;22(6):765-80. (PMID: 23238013); Nat Rev Cancer. 2015 May;15(5):302-10. (PMID: 25855404); Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10860-5. (PMID: 20505120); Cancer Res. 1993 Dec 1;53(23):5822-7. (PMID: 7694795); Int J Mol Sci. 2021 Mar 30;22(7):. (PMID: 33808496); Nature. 2024 Jun;630(8016):493-500. (PMID: 38718835); Surg Neurol. 2008 Dec;70(6):562-8; discussion 568-9. (PMID: 18614215); Signal Transduct Target Ther. 2022 Feb 2;7(1):33. (PMID: 35105853); J Mol Biol. 2016 Feb 22;428(4):720-725. (PMID: 26410586); Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W605-10. (PMID: 15980546); Biomolecules. 2022 Jul 28;12(8):. (PMID: 36008944); Curr Cancer Drug Targets. 2011 Nov;11(9):1082-97. (PMID: 21933105); Cell. 2013 Oct 10;155(2):462-77. (PMID: 24120142); Front Oncol. 2019 Sep 26;9:963. (PMID: 31616641); Biophys J. 2018 Feb 6;114(3):577-583. (PMID: 29414703); PLoS One. 2021 Jun 25;16(6):e0253760. (PMID: 34170922); Trends Mol Med. 2013 May;19(5):281-91. (PMID: 23537753); Discov Oncol. 2024 Sep 27;15(1):501. (PMID: 39331302); J Biotechnol. 2016 Jul 20;230:34-9. (PMID: 27188956); Cytokine Growth Factor Rev. 2015 Feb;26(1):1-6. (PMID: 24933439); Int J Biochem Mol Biol. 2013 Mar 31;4(1):27-40. (PMID: 23638319); Bioinformatics. 2015 Feb 1;31(3):423-5. (PMID: 25273103); PLoS One. 2019 Apr 9;14(4):e0211756. (PMID: 30964875); Nucleic Acids Res. 2007;35(22):7626-35. (PMID: 17981839); Mol Ther Nucleic Acids. 2019 Dec 6;18:99-109. (PMID: 31541799); Nat Rev Drug Discov. 2006 Feb;5(2):123-32. (PMID: 16518379); Cold Spring Harb Symp Quant Biol. 2019;84:21-30. (PMID: 32295929); Commun Biol. 2018 Feb 22;1:15. (PMID: 30271902); Methods Mol Biol. 2008;419:53-67. (PMID: 18369975); Oncogene. 2021 Apr;40(14):2483-2495. (PMID: 33686241); Methods. 2016 Jul 1;103:120-7. (PMID: 27016145); Int J Mol Sci. 2019 Aug 23;20(17):. (PMID: 31450739); Bioinformatics. 2009 Aug 1;25(15):1974-5. (PMID: 19398448); Angew Chem Int Ed Engl. 2012 Nov 19;51(47):11863-6. (PMID: 23055396); Ophthalmology. 2021 Apr;128(4):576-586. (PMID: 32882310); RNA. 2017 May;23(5):712-720. (PMID: 28202709); Neuro Oncol. 2015 Jul;17(7):992-8. (PMID: 25758746); Mol Ther Nucleic Acids. 2013 Jun 11;2:e98. (PMID: 23756353); Nature. 2008 Mar 6;452(7183):51-5. (PMID: 18322526); Mol Cancer. 2006 Dec 02;5:67. (PMID: 17140455); Genes (Basel). 2013 Jul 01;4(3):334-57. (PMID: 24705208); J Chem Phys. 2007 Jan 7;126(1):014101. (PMID: 17212484); Nucleic Acids Res. 2014 Dec 1;42(21):13306-14. (PMID: 25355509); Sci Rep. 2016 Feb 22;6:21285. (PMID: 26899418); Nat Rev Drug Discov. 2017 Mar;16(3):181-202. (PMID: 27807347); PLoS One. 2011;6(9):e24657. (PMID: 21949741); Neuro Oncol. 2015 Jul;17(7):910-1. (PMID: 25964312); Proteins. 2004 May 1;55(2):351-67. (PMID: 15048827) |
| Substance Nomenclature: | 0 (Aptamers, Nucleotide); EC 2.7.10.1 (Receptor, EphA2); 0 (Antineoplastic Agents) |
| Entry Date(s): | Date Created: 20250523 Date Completed: 20250609 Latest Revision: 20250613 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12152952 |
| DOI: | 10.1021/acs.jcim.5c00295 |
| PMID: | 40408544 |
| Database: | MEDLINE |
Journal Article